Alzheimer's disease (AD) is a major national health problem affecting approximately 4 million Americans. The primary barrier to progress in preventing and treating AD is a lack of understanding of the pathogenesis/etiology. The program project consists of 4 projects and 1 supportive Administrative Core containing a biostatistical and data management component. The project will utilize short postmortem interval AD and control brain specimens, animal models and primary neuronal cultures. The overall hypothesis to be investigated by this program is that oxidative insults play a central role in the pathogenesis of AD. Several specific hypotheses to be tested are a) amyloid beta peptide (Abeta) damages neurons by inducing reactive oxygen species (ROS) which impairs key enzyme functions, transport systems and lipids important in maintenance of cellular ion homeostasis and energy metabolism, b) oxidative injury to the brain activates neuroprotective genetic programs including production of cytokines and secreted forms of beta-amyloid precursor protein (sAPP) which protect neurons against oxidative insults and stabilize neuron calcium homeostasis, and c) alterations in trace element concentrations such as Fe, Cu, Al, Hg and others enhance oxidative stress and neuronal injury n AD. The first Project will investigate the mechanisms of ROS formation from Abeta using electron paramagnetic resonance. It will determine the critical amino acids in Abeta peptides essential for free radical generation and whether the radical is oxygen or carbon centered. The second Project will determine the effect of Abeta-induced free radical formation on neuronal degeneration and regional vulnerability in the AD brain and the qualitative difference in Abeta-induced oxidation compared with other ROS generators. The third Project will investigate the hypothesis that activation of cellular signaling systems involving tumor necrosis factor, sAPP and the transcription factor complex, NFKB, protect neurons against Abeta toxicity and other oxidative insults involved in the pathogenesis of AD. The fourth Project will test the hypothesis that elevated iron (Fe) and other trace elements catalyze ROS formation enhancing oxidative alterations in biomolecules which play a role in the pathogenesis of neuron degeneration in AD. The project is closely linked to the University of Kentucky Alzheimer's Disease Research Center which provides clinical and neuropsychological test data, brain tissue and diagnoses on AD and control subjects. An administrative Core provides supervision, coordination and statistical support of the program project. Our hypothesis of free radical based neuron degeneration offers possible therapeutic strategies in AD involving brain-accessible free radical scavengers.